EP0186551A1 - Médicament comportant en tant qu'association au moins une immunotoxine et au moins un polymère contenant du mannose - Google Patents

Médicament comportant en tant qu'association au moins une immunotoxine et au moins un polymère contenant du mannose Download PDF

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Publication number
EP0186551A1
EP0186551A1 EP85402319A EP85402319A EP0186551A1 EP 0186551 A1 EP0186551 A1 EP 0186551A1 EP 85402319 A EP85402319 A EP 85402319A EP 85402319 A EP85402319 A EP 85402319A EP 0186551 A1 EP0186551 A1 EP 0186551A1
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EP
European Patent Office
Prior art keywords
immunotoxin
mannan
chain
antibody
mannose
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Application number
EP85402319A
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German (de)
English (en)
French (fr)
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EP0186551B1 (fr
Inventor
Pierre Casellas
Bernard Rés. du Plan des 4 Seigneurs Bourrie
Pierre Gros
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Sanofi SA
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Sanofi SA
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Priority to AT85402319T priority Critical patent/ATE49708T1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/81—Packaged device or kit

Definitions

  • the therapeutic effects of activated or not activated immunotoxins can only be fully manifested insofar as the immunotoxin can, by its antibody part, localize in vivo, in active form, on the cell target to be destroyed (condition sine qua non any expression of immunotoxin activity).
  • the ability of the immunotoxin to locate on the target depends primarily on the ability of the immunotoxin to remain in the bloodstream and the extracellular fluids in active form for sufficient time to reach its target. cell target and at concentrations high enough for the occupancy rate of the corresponding antigenic sites to be high.
  • the Applicant has carried out numerous studies which have made it possible to establish the kinetics of plasma elimination of immunotoxins after intravenous injection in various animal models. It appeared that, after injection, the plasma level of biologically active immunotoxin decreases very quickly and very significantly. Thus, typically, in the rabbit, in a model using an immunotoxin constructed by coupling, using an arm with a disulfide bridge, the ricin A chain to a monoclonal antibody directed against the T65 antigen of human T lymphocytes, it appears that 97X of the immunotoxin present in the blood circulating at time 0 of the injection disappear in 30 min and 99.9% in 17 h.
  • the subject of the present invention is a drug combination which makes it possible to inhibit the rapid elimination of immunotoxins from the plasma after injection, without the intrinsic properties characteristic of immunotoxins being affected.
  • mannans represent a type of substance which is particularly advantageous for increasing the plasma levels of immunotoxins.
  • the term mannan is used here to designate any carbohydrate polymer, polysaccharide or polysaccharide, of average molecular weight greater than 1000 comprising a large proportion of mannose residues and more particularly from 20 to 100% of mannose residues, whatever the type of osidic sequence connecting these mannose residues to each other or to other sugars.
  • natural mannans isolated from yeasts for example Saccharomyces cerevisiae.
  • the protein-mannan complex is a mixture of macromolecules in which the polysaccharide component represents 50 to 90X of the complex.
  • the mannan fraction is itself a polymer of D-mannose. It is made up of an armature of mannose residues coupled in position a 1 ⁇ 6 to which are added side chains of different lengths comprising ⁇ 1 ⁇ 3 and ⁇ 1 ⁇ 2 links.
  • mannan used at doses where it does not present in itself, nor in combination with the immunotoxin any toxicity for the animal, makes it possible to increase in an extremely important way (by a factor of the order of 100) and lasting the plasma concentration of immunotoxins, which considerably improves their localization on the target and avoids binding inhibition phenomena due to the presence of free antibodies in the preparations, as indicated above .
  • the conjugate preferentially localizes in the liver. It is the same for the chain A which follows the same fate when it is injected in uncoupled form. This strongly suggests that the immunotoxin binds to the liver through the ricin A chain it contains. It is known that the ricin chain A is a glycoprotein whose polysaccharide groups include mannose and N-acetylglucosamine residues, the mannose residues being in the terminal position (Agri. Biol. Chem. (1978) 42, 501). It has also been established the existence in the liver of receptors capable of recognizing glycoproteins having such terminal mannose residues.
  • glycoproteins recognized by these receptors - present essentially on Kupffer's cells - are rapidly eliminated from the blood circulation by fixation on these cells which metabolize them. This is well documented in particular in the case of p- glucuronidase, as well as in the case of ribonuclease B (Arch. Biochem. Biophys. (1978) 188, 418; Advances in Enzymology Meister A. Ed New York (1974); Pediat. Res. (1977) 11, 816).
  • mannanes to inhibit the rapid plasma elimination of ricin A chain immunotoxins applies equally, for the reasons indicated above, to the uncoupled ricin A chain or to any hybrid, natural or semi-molecule synthetic, containing the ricin A chain and, in particular, to all the immunotoxins containing the ricin A chain, whatever the type of binding chosen to link the antibody to the ricin A chain.
  • This property of mannans applies more generally for the same reasons to any immunotoxin, whatever the toxin used to produce it, if this toxin or toxic subunit contains polysaccharide groups containing mannose residues, in particular in the terminal position , whatever the constitutive antibody and whatever the type of binding chosen to bind the antibody to the toxin or toxic subunit.
  • the purpose of this example is to demonstrate the modifications in the kinetics of elimination of the immunotoxins (as well as of those of their constituent elements) in the presence or in the absence of mannan.
  • the conjugate called IT-T101 is obtained by reaction between an antibody against human T cells (antibody T101 directed against the T65 antigen) substituted by an activated disulfide group and the ricin A chain.
  • the preparation and the cytotoxic properties of this conjugate have been described in French patent application No. 8121836 of the applicant.
  • the IT-T101 conjugate is administered to rabbits as a single injection into an ear vein. The amount injected corresponds to 1.25 mg of immunotoxin per kg of body weight, ie 0.415 mg / kg expressed in chain A, and 0.835 mg / kg expressed in antibody. Blood samples are taken over time on heparin. The plasmas are analyzed using an immunoradiometric test below designated by the abbreviation IRM-1.
  • This technique has the advantage of assaying the immunotoxin without modifying it.
  • This assay is carried out in microtiter plates (for example: "NUNC-TSP screening system” Poly Labo Block, France) whose cover is provided with hyper-absorbent tips which plunge into the wells of the base. These points constitute the solid phases.
  • Ricin antichain A sheep antibodies hereinafter referred to as Acl
  • Acl purified by affinity chromatography, are adsorbed on the solid phases. For this, 200 ⁇ l of a 10 ⁇ g / ml Acl solution in 20 mM phosphate buffer pH 7, 150 mM NaCl are distributed in the wells.
  • the tips are brought into contact first with the Acl solution for 24 h at 4 ° C and then with fetal calf serum for 3 h at 20 ° C to saturate all the binding sites.
  • the saturated immunosorbent is then brought into contact for 3 h at 20 ° C. with the plas samples. matics at different dilutions or with IT-T101 immunotoxin solutions of known concentrations to restore the calibration curve. Washing is carried out with a 20 mM phosphate buffer, pH 7, 150 mM NaCl, then the immunoabsorbent is brought into contact for 2 h at 20 ° C. with goat anti-mouse IgG antibodies purified by affinity chromatography and radiolabelled ( hereinafter designated by the abbreviation Ac2).
  • Radiolabelling of Ac2 is carried out with iodine 125 in the presence of chloramine T according to the method of Greenwood and Hunter (Biochem. J., (1963) 89, 114); the specific activity of radiolabelled Ac2 is 5 to 10 ⁇ Ci / mg. 10 6 cpm of radiolabelled Ac2 are introduced under 200 ml in a 20 mM phosphate buffer pH 7, 150 mM NaCl, 0.1X bovine serum albumin. After washing, in 20 mM phosphate buffer pH 7, 150 mM NaCl, the tips are detached and the amount of bound Ac2 is measured by counting the radioactivity. The measurement of the immunotoxin concentration in the samples to be assayed is made by reference to the calibration curve carried out with IT-T101 introduced at different known concentrations.
  • This antibody was prepared and purified as indicated in French patent application No. 8121836.
  • the T101 antibody is injected into rabbits intravenously at a dose of 0.835 mg / kg. Plasma samples are taken as before.
  • the antibody concentration in the samples is measured by radioimmunometric assay (MRI-2).
  • MRI-2 radioimmunometric assay
  • This test is carried out under the same conditions as the MRI-1 test, except that the Acl solution is here a 10 mg / ml solution of goat anti-mouse IgG antibodies purified by affinity chromatography.
  • the Ac2 antibody is identical to that of the MRI-1 test. Measuring the con centering in T101 antibody in the samples to be assayed is done by reference to the calibration curve carried out with the T101 antibody introduced at different known concentrations.
  • the ricin chain A was prepared and purified as indicated in prior French patents No. 78/27838 and addition No. 79/24655.
  • the A chain is injected into the rabbit intravenously at a dose of 0.415 mg / kg. Plasma samples are taken as before.
  • the concentration of chain A in the samples is measured by immunoradiometric assay (MRI-3).
  • This test is carried out under the same conditions as the IRM-1 test, the Acl antibodies, absorbed on the solid phase, also being ricin-antichain A sheep antibodies purified by affinity chromatography and the Ac2 antibodies being the same radiolabeled antibodies as described in IRM-1 ⁇
  • the measurement of the ricin A chain concentration in the samples to be assayed is done by reference to a calibration curve carried out with the ricin A chain introduced at different known concentrations.
  • the detection threshold for these three products is 1 ng / ml.
  • the study of intra- and inter-test reproducibility gives coefficients of variation less than 10X for the concentration values in the range from 1 to 200 ng / ml.
  • Figure 1 shows the plasma elimination curve of IT-T101 which has two phases (curve 1). In the first phase, the product disappears quickly (around 97% in 30 min); in the second phase, the decrease is slower. The first elimination phase observed with IT-T101 does not appear in the elimination kinetics of the T101 antibody where only a slow elimination phase is recorded (curve 2). On the other hand, the kinetics of plasma elimination from the uncoupled A chain is very comparable to that of IT-T101: 1 h after the injection, only 0.7% of the administered dose remains in the plasma. (curve 3).
  • Figure 2 shows the plasma elimination curve as a function of time of IT-T101 injected intravenously in association with mannan at the total dose of 0.416 g / kg (curve 2).
  • the first phase of elimination - responsible for the disappearance of most of the product - is practically abolished, which leads to a major increase in the level of active plasma immunotoxin.
  • the concentration of IT-T101 is 100 times higher, when the immunotoxin has been combined with mannan, than it is in the absence of mannan (curve 1).
  • This example demonstrates the hepatic uptake of the ricin A chain after intravenous injection and the inhibition of this uptake by mannan.
  • the i-125 radiolabelled A chain is injected into Charles River France CD1 mice intravenously in the absence or presence of mannan at a dose of 1 g / kg.
  • two animals are anesthetized.
  • the abdominal cavity is open, the vena cava sectioned, the liver is washed with 10 ml of physiological water by injection into the portal vein.
  • the entire liver is removed and the radioactivity is determined.
  • the results are represented as a percentage of the number of cpm fixed on the liver relative to the number of total cpm injected (FIG. 5).
  • the ricin A chain is very early and efficiently picked up by the liver as indicated by the peak of radioactivity.
  • the cytotoxicity was evaluated by measuring the incorporation of 14C-leucine by the target cells (CEM cells) after 24 h of incubation at 37 ° C. in the presence of known concentrations of the immunotoxin studied, or of reference cytotoxic substances, in the absence or presence of mannan at a concentration of 10 mg / ml.
  • the technique used is that previously described (J. Biol. Chem. 1984, 259 (15), 9359).
  • the immunotoxin alone or in its form activated by ammonium chloride fully retains its activity. Likewise, the intrinsic toxicity of chain A is not modified. Thus, in the presence of mannan, the characteristic cytotoxicity properties of the immunotoxin are not altered.
  • the purpose of this example is to demonstrate the effect of mannan on the action of an immunotoxin in an "in vivo" test.
  • the immunotoxin used is the conjugate associating, by a disulfide bond, the anti-Thy 1.2 antibody (antibody AT15E) and the A chain of Ricine and prepared according to the process described in the French patent applications in the name of the applicant and cited above. .
  • mice receive by intravenous injection on day 0.5 x 10 4 T2 cells (Thy 1.2 positive murine lymphoma cells) and are randomized before treatment.
  • the animals are observed for 50 days and mortality is noted.
  • Figure 6 gives the percentage of surviving animals as a function of the time elapsed after treatment.
  • Curve 1 concerns the animals which received the immunotoxin alone and curve 2 the animals which received the immunotoxin plus mannan combination.
  • the immunotoxin-mannan association gave 90% of survivors 50 days after the treatment whereas the administration of immunotoxin alone gave only 30% of animals surviving after 50 days.
  • the combination constituted by an immunotoxin and mannan can be used for the treatment of conditions, cancerous or not, whose target cells are recognized by the antibody used for the preparation of the immunotoxin.
  • the treatment should be carried out with a sufficient dose of immunotoxin associated with an amount of mannan which can vary from 10 mg to 1 g / kg each time the immunotoxin is administered.
  • the optimal methods of administration of the constituents of the association as well as the duration of treatment must be determined in each case depending on the subject and the nature of the condition to be treated.
  • the new drugs according to the invention are packaged for use by the injectable route and, preferably, by the intravenous route.
  • the constituents of the association will be kept separate and can be mixed if necessary only at the time of use, in the syringe or infusion solvent.
EP85402319A 1984-11-29 1985-11-27 Médicament comportant en tant qu'association au moins une immunotoxine et au moins un polymère contenant du mannose Expired - Lifetime EP0186551B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85402319T ATE49708T1 (de) 1984-11-29 1985-11-27 Arzneimittel mit gehalt an einer mischung von mindestens einem immunotoxin und mindestens einem mannose enthaltenden polymer.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8418203A FR2573656B1 (fr) 1984-11-29 1984-11-29 Medicament comportant en tant qu'association au moins une immunotoxine et au moins un polymere contenant du mannose
FR8418203 1984-11-29

Publications (2)

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EP0186551A1 true EP0186551A1 (fr) 1986-07-02
EP0186551B1 EP0186551B1 (fr) 1990-01-24

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EP85402319A Expired - Lifetime EP0186551B1 (fr) 1984-11-29 1985-11-27 Médicament comportant en tant qu'association au moins une immunotoxine et au moins un polymère contenant du mannose

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US (1) US4749566A (it)
EP (1) EP0186551B1 (it)
JP (1) JPH062679B2 (it)
AT (1) ATE49708T1 (it)
AU (1) AU588008B2 (it)
CA (1) CA1254139A (it)
DE (1) DE3575521D1 (it)
DK (1) DK163030C (it)
FR (1) FR2573656B1 (it)
IE (1) IE58776B1 (it)
IL (1) IL77168A0 (it)
NZ (1) NZ214357A (it)
ZA (1) ZA859120B (it)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010140A1 (en) * 1988-04-22 1989-11-02 Cancer Research Campaign Technology Limited Further improvements relating to drug delivery systems
EP0362297A1 (en) * 1987-05-27 1990-04-11 Xoma Corporation Hepatic blocking agents
US5632990A (en) * 1988-04-22 1997-05-27 Cancer Research Campaign Tech. Ltd. Treatment for tumors comprising conjugated antibody A5B7 and a prodrug

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5185434A (en) * 1985-02-13 1993-02-09 Sanofi Prolonged-action immunotoxins containing a glycopeptide constituent which inactivates ribosomes, modified on its polysaccharide units
ATE81467T1 (de) * 1987-02-24 1992-10-15 Xoma Corp Immunosuppression bei der auf immunotoxin basierten behandlung von menschen.
US5112607A (en) * 1991-06-05 1992-05-12 The United States Of America As Represented By The Secretary Of The Army Potentiation of immunotoxin action by Brefeldin A
FR2802536B1 (fr) * 1999-11-23 2003-06-13 Chru Lille Oligomannosides de synthese, leur preparation et leur utilisation a la detection d'anticorps et a la prevention d'infections
US20060263415A1 (en) 2005-05-05 2006-11-23 Sensient Flavors Inc. Production of beta-glucans and mannans
CN102985095B (zh) * 2010-05-10 2016-05-18 埃森德生物制药有限公司 免疫刺激组合物和疫苗组合物
US20120177567A1 (en) * 2010-08-11 2012-07-12 National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs), U.S. Government Methods of Treating Pediatric Acute Lymphoblastic Leukemia with an Anti-CD22 Immunotoxin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080401A1 (fr) * 1981-11-20 1983-06-01 Elf Sanofi Nouveaux médicaments anticancéreux pour le traitement des leucémies T constitués de la chaine A de la ricine et d'un anticorps monoclonal spécifique
EP0086152A1 (fr) * 1982-02-09 1983-08-17 Sanofi S.A. Médicaments comportant en tant qu'association au moins une immunotoxine et au moins un ionophore carboxylique monovalent
EP0088694A1 (fr) * 1982-03-10 1983-09-14 Elf Sanofi Médicament cytotoxique formé de l'association d'au moins une immunotoxine et de la chloroquine
EP0089270A1 (fr) * 1982-03-11 1983-09-21 Elf Sanofi Médicaments cytotoxiques comportant au moins une immunotoxine et une amine
EP0089880A1 (fr) * 1982-03-17 1983-09-28 Sanofi S.A. Nouveaux conjugués associant, par liaison covalente, une enzyme et un anticorps, et associations médicamenteuses utilisant lesdits conjugués

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2504010B1 (fr) * 1981-04-15 1985-10-25 Sanofi Sa Medicaments anticancereux contenant la chaine a de la ricine associee a un anticorps antimelanome et procede pour leur preparation
FR2577135B1 (fr) * 1985-02-13 1989-12-15 Sanofi Sa Immunotoxines a longue duree d'action comportant un constituant glycopeptidique inactivant les ribosomes modifie sur ses motifs polysaccharidiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080401A1 (fr) * 1981-11-20 1983-06-01 Elf Sanofi Nouveaux médicaments anticancéreux pour le traitement des leucémies T constitués de la chaine A de la ricine et d'un anticorps monoclonal spécifique
EP0086152A1 (fr) * 1982-02-09 1983-08-17 Sanofi S.A. Médicaments comportant en tant qu'association au moins une immunotoxine et au moins un ionophore carboxylique monovalent
EP0088694A1 (fr) * 1982-03-10 1983-09-14 Elf Sanofi Médicament cytotoxique formé de l'association d'au moins une immunotoxine et de la chloroquine
EP0089270A1 (fr) * 1982-03-11 1983-09-21 Elf Sanofi Médicaments cytotoxiques comportant au moins une immunotoxine et une amine
EP0089880A1 (fr) * 1982-03-17 1983-09-28 Sanofi S.A. Nouveaux conjugués associant, par liaison covalente, une enzyme et un anticorps, et associations médicamenteuses utilisant lesdits conjugués

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362297A1 (en) * 1987-05-27 1990-04-11 Xoma Corporation Hepatic blocking agents
EP0362297A4 (en) * 1987-05-27 1990-11-07 Xoma Corporation Hepatic blocking agents
WO1989010140A1 (en) * 1988-04-22 1989-11-02 Cancer Research Campaign Technology Limited Further improvements relating to drug delivery systems
US5632990A (en) * 1988-04-22 1997-05-27 Cancer Research Campaign Tech. Ltd. Treatment for tumors comprising conjugated antibody A5B7 and a prodrug
US5683694A (en) * 1988-04-22 1997-11-04 Cancer Research Campaign Tech. Ltd. & Zeneca Ltd. Method for the treatment of tumors with conjugated antibody A5B7 and a prodrug

Also Published As

Publication number Publication date
IE852992L (en) 1986-05-29
AU588008B2 (en) 1989-09-07
NZ214357A (en) 1990-02-26
US4749566A (en) 1988-06-07
ATE49708T1 (de) 1990-02-15
DK554585D0 (da) 1985-11-29
DK163030B (da) 1992-01-13
FR2573656B1 (fr) 1987-02-27
AU5047385A (en) 1986-06-05
DK554585A (da) 1986-05-30
FR2573656A1 (fr) 1986-05-30
JPH062679B2 (ja) 1994-01-12
EP0186551B1 (fr) 1990-01-24
DE3575521D1 (de) 1990-03-01
IE58776B1 (en) 1993-11-17
IL77168A0 (en) 1986-04-29
CA1254139A (en) 1989-05-16
JPS61197528A (ja) 1986-09-01
DK163030C (da) 1992-06-15
ZA859120B (en) 1986-08-27

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